For operations in the fields of oral surgery and dental treatment, in particular, for tooth extraction and other in dental treatment, anesthetics for local injection (agents for local anesthesia) containing lidocaine (2-diethylamino-N-(2,6-dimethyl-phenyl)acetamide) as an active ingredient have been used. For example, "Xylocaine.RTM. Cartridge for Dental Use" (Fujisawa Pharmaceutical Co., Ltd.) is clinically used. This agent for local anesthesia is a composition for topical administration which contains 20 mg of lidocaine hydrochloride and 0.0125 mg of epinephrine per 1 ml of parenteral solution. The agent is usually used in an amount of 0.3-1.8 ml to carry out infiltration anesthesia or block anesthesia (see, a package insert of the drug).
Agents for local anesthesia are generally formulated with a catecholamine such as epinephrine which has angiotonic effect on local capillary blood vessels to reduce blood flow. The effect of the catecholamine is to decrease bleeding in a filed of operation by lowering blood flow, and to reduce transmigration (diffusion) of an anesthetic agent being an active ingredient into blood and maintain high concentration of the anesthetic agent in the local tissue to achieve a prolonged local anesthetic effect (Collins, V. J., Principles of Anesthesiology, 2nd Ed., Lea and Febiger, Philadelphia, 1976; as a review about agents for dental local anesthesia, see, Dental Outlook, special edition, "Medical practice of tooth extraction," 4. Dental local anesthetics, pp.84-94, 1979).
However, when the aforementioned agent for local anesthesia is used for dental operations such as tooth extraction, which may be completed in a short period of time such as in several to 10 minutes, the local anesthetic effect tends to be maintained longer than required. In a consequence, oral and glossal benumbedness may remain several hours after the operation, and difficulties may arise in eating and drinking. In addition, a catecholamine such as epinephrine constricts blood vessels to decrease blood flow in a tissue and increases local oxygen consumption. For this reason, when vasoconstriction is maintained for longer hours than needed, tissue necrosis and delay of wound healing may possibly be caused. Accordingly, a development of an agent for local anesthesia has been desired which have a duration suitable for short-time operations such as tooth extraction.
A content ratio of a catecholamine added to a local anesthetic is generally recommended to be around 1/50,000-1/200,000 (g/ml) based on the volume (ml) of a local anesthetic agent (see, the above-described "Dental Outlook," special edition, "Medical practice of tooth extraction," p.92, right column), and dental lidocaine preparations which have been clinically used so far contain 1/80,000 (g/ml, 0.0125 mg/ml) of epinephrine. The inventor of the present invention conducted various studies to provide an agent for local anesthesia which has a duration suitable for short-time dental operations such as tooth extraction, and as a result, they found that a necessary and sufficient duration of local anesthetic action for a dental anesthesia can be achieved by adding about 1/200,000 of epinephrine (g/ml, 0.005 mg as a free base per ml).
Catecholamines such as epinephrine and norepinephrine are known to be unstable under neutral or alkaline conditions, and readily oxidized by an oxidizing agent such as oxygen, and colored to give a red or pale red to brown solution (Fukushima et al., "Incompatibilities of Parenteral Injections," published by Fuji Print Co., Ltd., Press Dept., 1982, Section of "Adrenal Hormone Preparations", pp.384-395). Grubstein et al. (Grubstein, B. and Milano, E., Drug Development and Industrial Pharmacy, 18, pp.1549-1566, 1992) reported an issue of stabilization of epinephrine formulated in local anesthetics.
The aforementioned "Xylocaine.RTM. Cartridge for Dental Use" (Fujisawa Pharmaceutical Co., Ltd.) containing epinephrine is formulated with sodium pyrosulfite as an anti-oxidant in a content ratio of 0.6 mg per ml to prevent the oxidation of epinephrine. There are also known a formulation comprising a dental local anesthetic composition containing lidocaine and epinephrine added with dried sodium sulfite as an anti-oxidant ("Xylestesin A," Hakusui Trading, Co., Ltd.), and a formulation comprising a dental local anesthetic composition containing lidocaine and norepinephrine (0.04 mg per 1 ml) added with dried sodium sulfite as an anti-oxidant ("Xylestesin," Hakusui Trading Co., Ltd.).
The inventors of the present invention conducted studies to provide a composition for local anesthesia suitable for tooth extraction or the like by decreasing a content of a catecholamine based on lidocaine. In the course of the studies, they found that the oxidative degradation of a catecholamine was remarkably accelerated by lowering the content of a catecholamine such as epinephrine. They also found that catecholamines are extremely unstable to oxidation in a composition for anesthesia containing a catecholamine in an amount of about 1/200,000 (W/V: g/ml, 0.005 mg as a free base per 1 ml), and that it is quite difficult to store the composition stably by using sodium pyrosulfite or dried sodium sulfite which is conventionally used as an antioxidant. These problems have not been suggested or taught to date in the field of the art.
Grubstein et al. as mentioned above (Grubstein, B. and Milano, E., Drug Development and Industrial Pharmacy, 18, pp.1549-1566, 1992) discloses the results of stabilization of epinephrine in formulations containing pyrosulfite and citric acid in combination (Table1, Code D). However, these results are not unexpectedly superior to the results obtained by using pyrosulfite alone. In addition, the results neither suggest nor teach stabilizing effect of citric acid for epinephrine. Furthermore, these results were obtained by formulations containing epinephrine in an amount of 1/80,000 (W/V), and do not teach the fact that the stability of epinephrine is markedly reduced with decreasing amount of epinephrine.
A package insert (published in January, 1994) of Xylocaine.RTM. (lidocaine HCl injection, USP), an agent for dental local anesthesia sold by Astra USA, Inc., Westborough, Mass., USA, describes in Table 1 an aqueous solution containing lidocaine (2%) and epinephrine at a concentration of 1/100,000 or 1/50,000 (g/ml) together with citric acid (0.2 mg/ml). However, the package insert neither suggests nor teaches an action of citric acid contained in the aqueous solution. Furthermore, the agent for local anesthesia also contains epinephrine at a high concentration, and therefore, the product does not teach the fact that the stability of epinephrine is markedly reduced with decreasing amount of epinephrine.